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Near Normalization of Final Height with Adapted Doses of Growth Hormone in Turner’s Syndrome

Department of Pediatric Endocrinology and INSERM U-342 (J.-C.C., L.M., C.G., J.-L.C.), Hôpital Saint Vincent de Paul, Paris; and Laboratoire Sanofi-Winthrop (C.G., J.-P.D.), Paris, France

Address all correspondence and requests for reprints to: Dr. Jean-Claude Carel, INSERM U-342, Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France. E-mail: carel{at}cochin.inserm.fr

	Abstract

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An adapted GH dose regimen was evaluated in 14 untreated patients with Turner’s syndrome. The initial GH dose (0.7 U/kg·BW) was increased by 0.7 U/kg·BW, up to a maximum of 2.1 U/kg·BW, when growth velocity (GV) declined to less than 200% of the pretreatment level. These patients were compared to a group of 17 patients with similar initial characteristics, who received a fixed dose of 0.9 U/kg·BW GH. Tolerance to both GH regimens was excellent. The adapted GH doses only partially prevented the waning effect observed with conventional doses of GH, and the initial goal of doubling GV was only achieved in 42% of the 112 patient-semesters. Doubling the GH dose from 0.7 to 1.4 U/kg·BW increased the GV by 1.6 ± 1.8 cm/yr (P < 0.006); increasing the GH dose from 1.4 to 2.1 U/kg·BW increased GV by 0.8 ± 1.3 cm/yr (P = NS). The overall height gain during the 4-yr trial was 25.6 ± 3.9 cm in the adapted dose group and 21.8 ± 3.9 cm in the conventional group (P < 0.02). Final height (FH) results were obtained in 12 of 14 patients in the adapted dose group and all 17 patients in the conventional group and compared to the predicted FH using Lyon’s method. The estimated height benefit was 10.6 ± 3.8 cm in the adapted dose group compared to 5.2 ± 3.7 cm in the conventional group (P < 0.01). Eighty-three percent of the patients in the adapted dose group had an FH superior or equal to -2 SD score for the general population compared to 29% in the conventional group. In conclusion, a marked increment in the GH dose in girls with Turner’s syndrome associated with a relatively late age at introduction of estrogen therapy brought 83% of the patients into the lower range of the normal height distribution of the general population.

	Introduction

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UNTREATED patients with Turner’s syndrome (TS) have final heights (FH) well below -2 SD for the general population (1, 2, 3). For instance, in France, TS patients have FH of 141.1 ± 6.4 (4), 142.1 ± 5.6 (5), or 142.5 ± 4.9 (6) cm, corresponding to -3.4 to -3.7 SD score for the general population (7). GH increases growth velocity (GV) in patients with TS (1, 8, 9, 10), and GH is now registered for this indication in several countries. Most reports indicate an increased average FH in treated patients compared with untreated historical controls or with predicted heights (11, 12). However, the estimated height gains have been relatively modest, ranging from 2.8–8.5 cm, with mean FH still well below -2 SD score (13, 14, 15, 16, 17, 18). In addition, one report has failed to demonstrate a positive effect of GH on FH, questioning the soundness of its usage (19, 20). The available data clearly show a need for improvement of growth results in TS.

In most reported studies, using fixed doses of 0.7–1 U/kg·BW (3), GV declined after 1–2 yr of GH treatment, limiting the ability to continuously increase the height SD score over the years. We report the result of a study aimed at improving catch-up growth by adapting the GH dose during the first 4 yr of treatment. The initial GH dose (0.7 U/kg·BW) was increased by 0.7 U/kg·BW, up to a maximum of 2.1 U/kg·BW, when GV declined to less than 200% of the pretreatment level. This group was compared to conventionally treated patients who received a fixed GH dose of 0.9 U/kg·BW.

	Subjects and Methods

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Two nonrandomized groups of patients with TS treated with recombinant GH (Maxomat, Sanofi, Paris, France) were analyzed with the following inclusion criteria: age at onset of treatment between 6 and 15 yr and projected height using the method of Lyon (21) of -2 SD score or less for the general population. Group 1 (conventional) comprised 17 girls who received 0.9 U/kg·BW GH in daily injections. Group 2 (adapted dose) comprised 14 girls for whom the initial dose of 0.7 U/kg·BW was increased by 0.7 U/kg·BW every 6 months if GV in the previous semester was 200% or less of the pretreatment GV. The maximum GH dose was 2.1 U/kg·BW. After 4 yr, the GH dosage was decreased to 0.9 U/kg·BW. In both groups, GH treatment was interrupted when bone age (22) was 13.5 yr or more. The patients and families of the adapted dose group gave their informed consent before participating in the trial, which was approved by the local ethical committee. Preliminary results have been presented previously (23).

Decision to initiate sex steroid supplementation was made on an individual basis, weighing the desire for normal pubertal development and the risk of premature epiphyseal closure. In the adapted dose group, sex steroids were not initiated during the 4-yr protocol. Low doses of steroids were used in both groups, and none of the patients received oxandrolone.

SD scores of height were calculated using standards from the general population (7) and data collected by Lyon et al. (21) in untreated patients with TS. The validity of the method of Lyon (21) to accurately predict FH in French patients with TS has been validated in an independent set of patients (6). SD scores of GV were calculated using French TS standards (6). Insulin-like growth factor I (IGF-I) (24) and hemoglobin A_1c (HbA_1c; HPLC, normal values, 4.7 ± 0.7%) were measured every 3 months.

Statistical analysis was performed with StatView-4 software (Abacus Concepts, Berkeley, CA). Data are presented as the mean ± SD. Mann-Whitney and Wilcoxon tests were used for intergroup (unpaired) or intragroup (paired) comparisons.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Effect of adapted GH doses on growth parameters during the first 4 yr of treatment

The two groups of patients had similar initial characteristics (Table 1). Initiation of GH treatment at a dose of 0.7–0.9 U/kg·BW induced an acceleration of GV from 3.7 ± 0.8 to 7.2 ± 1.5 cm/yr (+3.3 ± 6.7 cm/yr or +2.9 ± 0.9 SD score, both groups combined). In the conventional treatment group, GV progressively declined with the duration of GH treatment (Fig. 1). This decline was still significant when GV was expressed as a SD score, taking into account the progressive decline in GV in untreated patients with TS (Fig. 1B). Patients in the adapted dose group received 1.5 ± 0.3 U/kg·BW during the 4-yr trial, and at the end of the trial, 79% received the highest dose, and 21% received the intermediate dose (Fig. 2). The adapted GH dose resulted in significantly higher GV than the fixed dose during the second semester and the third year of treatment (Fig. 1). GV was 2 SD score or greater during 67% of the semesters in the adapted dose group and 44% of the semesters in the conventional group (P = 0.0003, by ² test). However, our initial goal of doubling the pretreatment GV was only achieved in 12, 10, 8, 4, 5, 4, 3, and 1 of our 14 patients during the 8 consecutive semesters (42% of the 112 patient-semesters). During the fourth year, GV was 5.1 ± 1.4 cm/yr in the adapted dose group (P < 0.05 vs. pretreatment GV) and 4.4 ± 1.4 cm/yr in the conventional group (P = NS vs. pretreatment GV). We compared GV during the 6 months before and after the first and second increments in GH dose (Fig. 3); doubling the GH dose from 0.7 to 1.4 U/kg·BW increased GV by 1.6 ± 1.8 cm/yr or 2.9 ± 0.9 SD score (P < 0.006), whereas increasing the GH dose from 1.4 to 2.1 U/kg·BW increased GV by 0.8 ± 1.3 cm/yr or 0.7 ± 1.2 SD score (P = NS). This relatively small increase contrasts with the marked downward trend of GV in the conventional group.

View larger version (39K): [in this window] [in a new window]   Figure 1. GV (mean ± SD) expressed as centimeters per yr (A) or as the SD score of values of untreated TS patients (B) in the two groups of patients. , Adapted treatment; , conventional treatment. *, P < 0.01; **, P < 0.02 (vs. the conventional group).

View larger version (93K): [in this window] [in a new window]   Figure 2. Progressive increment in the GH dose in the adapted treatment group.

View larger version (20K): [in this window] [in a new window]   Figure 3. Effect of an increment in the GH dose on GV measured during the semester preceding and following the modification; individual data as well as the mean ± SD are presented. *, P < 0.006.

FH were evaluated in patients with bone ages of 13.5 yr or greater, with mean actual bone ages of nearly 16 and 15 yr in both groups, corresponding to all patients of the conventional group and 12 of 14 in the adapted dose group (Table 3). FH were significantly higher in the adapted dose than in the conventional group. Comparison of pretreatment predicted height and actual FH showed a 10.6 ± 3.8-cm increment in the adapted dose group and a 5.2 ± 3.7-cm increment in the conventional group (P < 0.01; Table 3 and Fig. 4). This height gain was 4 cm or more in all patients in the adapted dose group and in 13 of 17 patients in the conventional group. Compared to the general population, 10 of 12 patients (83%) in the adapted dose group had a FH superior or equal to -2 SD score compared to only 5 of 17 (29%) in the conventional group. In addition, the 2 patients in the adapted dose group who have not reached FH have current heights of 152.5 and 150 cm, with bone ages of 13 and 12.5 yr.

View larger version (28K): [in this window] [in a new window]   Figure 4. Comparison of predicted height before treatment and actual FH in the two groups of patients; individual data as well as the mean ± SD are presented. *, P < 0.01.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this report, we analyzed the growth characteristics of patients with TS, treated with two GH regimens. Patients who received the 4-yr adapted dose regimen gained, on the average, an additional 4 cm during the first 4 yr of GH treatment. These patients, followed to their near FH, gained an average of 10.6 cm over their predicted height, and 92% of them measured more than 150 cm.

Catch-up growth induced by the initiation of treatment is dose dependent in TS (9, 25, 26), but the initial acceleration of GV is invariably followed by a deceleration, a poorly understood phenomenon. Several strategies have been discussed to compensate for this secondary GH resistance: earlier age at initiation of treatment, use of higher initial doses (27), stepwise increment of GH dose (26), multiplication of injections (28, 29), or addition of sex steroids (15, 18). However, the analysis is complicated by several factors, such as increased bone age maturation with estrogens (30, 31) and possibly with GH (32) or oxandrolone (33). Our results confirm that during GH treatment, the growth response to similar increments in GH dose decreases (+3.3 vs. +1.6 vs. +0.8 cm/yr with doses increasing from 0 to 0.7, then to 1.4, and then to 2.1 U/kg·BW). An approach similar to ours was used by Van Teunenbroek et al. (26), who compared a fixed GH dose to stepwise increased doses. They observed a 3.3-cm, or 0.61 SD score, greater height gain with their highest compared to their lowest dose. These results are comparable to ours, although the highest dose used in their study was similar to our intermediate dose (1.4 U/kg BW). However, the patients treated by Van Teunenbroek et al. (26) were younger at the initiation of therapy than in our study (6.4 vs. 10.2 yr). Whether the improvement of results we have observed with adapted doses are due to the higher mean dose or to the dose adjustment itself remains to be determined.

Although final results are the most worthy goal of GH treatment in TS, their evaluation is methodologically difficult. The comparison with historical control groups has been criticized (12, 34), whereas prediction methods (21) are generally favored (6, 11, 12, 35). However, predicted FH using Lyon’s method seems to exceed the actual FH of untreated patients by 1.8–3.3 cm (19, 35). Using, this method, therefore, might underestimate the effects of GH treatment. Our results in the conventional group are similar to previously reported data for patients treated at a relatively late age (11 yr), with estimated height benefits averaging 5.2 cm. In contrast, the adapted dose treatment produced a 10.6 ± 3.8-cm increase in FH over predicted height, a result exceeding by at least 2 cm those of all other reported studies (13, 14, 15, 16, 17, 18, 19). It is noteworthy that the difference between the two groups at the end of the 4-yr trial (+4 cm) was maintained when FH was reached (+5.4 cm).

Estrogen therapy was introduced at a relatively late age in both groups of patients, and we believe that this contributed to the FH results we observed. Although the optimal age of introduction of estrogens in TS is still a matter of debate, the results of all studies converge to indicate that early introduction of estrogens has a deleterious effect on height (30, 31). Further studies are needed to evaluate the end results of such a delayed initiation of puberty in terms of psychological consequences as well as on the constitution of bone mass.

In conclusion, a marked increment in the GH dose in girls with TS only partially prevented the waning effect of the growth response. However, this 4-yr treatment regimen, associated with a relatively late age at introduction of estrogen therapy, produced a 10.6-cm estimated height gain and brought 83% of the patients into the lower range of the normal height distribution of the general population. Further studies will be needed to determine the best therapeutic modalities to obtain similar results while increasing cost-effectiveness and mimicking a physiological pubertal development.

	Acknowledgments

 
We thank Prof. Pierre Chatelain for performing IGF-I measurements, and Bernard Job (Sanofi) for his involvement at the early stages of the project.

Received July 17, 1997.

Revised January 15, 1998.

Accepted January 21, 1998.

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